Outsmarting Breast Cancer
Breast carcinogenesis is a multi-event process that occurs in a dynamic microenvironment. Unlike normal differentiated cells whose functions are under tight regulation, cancer cells are multitasking as a result of the hyperactivation of multiple intracellular signaling pathways and loss of tumor suppressors. In cancer cells, these pathways do not respond to normal regulatory signals but are manipulated simultaneously by more than one oncogenic signals. Besides these alterations in cancer cells, modification of the extracellular matrix and transformation of the stromal tissues are also involved in tumor progression and metastasis. Therefore, our rationale to suppress tumor progression includes: 1) simultaneous targeting of key oncogenic pathways expressed in cancer cells, and 2) targeting microenvironmental modifications that result from the crosstalk between oncogenic signaling networks in cancer cells.
MicroRNAs (miRNAs) are naturally occurring non-coding small RNA molecules of 21-24 nucleotides that can base pair to 3’UTR sites in the messenger RNAs (mRNAs) of protein-coding genes. Consistent with their regulatory function, miRNAs are crucial for development, differentiation, proliferation and apoptosis. In animals, each miRNA can downregulate the expression from hundreds of target mRNAs via mRNA degradation or block of translation. MiRNAs are frequently dysregulated in human cancers, and have shown promise as tissue-based markers for cancer classification and prognostication. Our group is actively investigating the mechanisms of miRNA dysregulation in breast cancer.
MiRNAs have been recently detected in the circulation of cancer patients, where they are associated with clinical parameters. Assessment of circulating miRNA profiles from breast cancer patients and correlation of these profiles with tumor traits (e.g., chemotherapy response) are therefore of great clinical interest. We have carried out discovery profiling of circulating small RNAs by deep sequencing using the pre-treatment sera of stage II–III breast cancer patients. More than 800 miRNA species were detected and exhibited patterns associated with the histopathological and molecular profiles of breast cancer. Our study indicates that certain miRNAs can serve as potential blood-based biomarkers for the clinical outcomes of breast cancer, and developing miRNA blood markers may allow optimized chemotherapy treatments and preventive anti-metastasis interventions in future clinical applications.
The critical roles of CSCs in cancer initiation, progression and therapeutic refractoriness have emerged in recent studies. Their regulation by factors in the tumor microenvironment, however, remains largely uncharacterized. Our group focuses on various environmental elements, such as the stromal fibroblasts, for their effect on breast cancer stem cells. We show that compared to normal fibroblasts, primary cancer-associated fibroblasts produce higher levels of chemokine (C-C motif) ligand 2 (CCL2), which stimulates the stem-cell-specific, sphere-forming phenotype in breast cancer cells and CSC self-renewal. Increased CCL2 expression in activated fibroblasts requires STAT3 activation by diverse cancer-secreted cytokines, and in turn, induces NOTCH1 expression and the CSC features in breast cancer cells, constituting a “cancer-stroma-cancer” signaling circuit. Our results are supported by a xenograft model of paired fibroblasts and tumor cells from primary human breast cancer. Regulation of NOTCH1 by CCL2 is further supported by a significant correlation between the expression profiles of the two genes in primary breast cancers, where upregulation of both genes is associated with poor differentiation. We are currently exploring the role of CCL2, STAT3 and NOTCH1 as potential therapeutic targets to block the cancer-host communication that prompts CSC-mediated disease progression and treatment resistance.